Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA210779 | ENA |
REPOSITORIES: ENA
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Project description:<p>We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor <i>CXCR4</i>. We have identified a patient born with WHIM syndrome and the WHIM mutation <i>CXCR4<sup>R334X</sup></i> who has been disease-free for 20 years and who lacks <i>CXCR4<sup>R334X</sup></i> in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele <i>CXCR4<sup>R334X</sup></i> and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective <i>Cxcr4</i> haploinsufficiency (inactivation of one copy of <i>Cxcr4</i> and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that <i>CXCR4</i> knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.</p>
| phs000856 | dbGaP
Project description:Erg is an ETS family transcription factor frequently overexpressed in human leukemias and has been implicated as a key regulator of hematopoietic stem cells (HSCs). However how Erg controls normal hematopoiesis, particularly at the stem cell level, remains poorly understood. Using homologous recombination, we generated an Erg knockdown allele (Ergkd) in which Erg expression can be restored upon Cre-mediated excision of a Stopper cassette. In Ergkd/+ mice, ~40% reduction in Erg dosage perturbed both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin-Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we found Erg-restored HSPCs outcompeted Ergkd/+ HSPCs for contributing to adult hematopoiesis in vivo. Intriguingly, HSC differentiation also appeared attenuated, leading to accumulation of long-term HSCs in the mutant LSK population. Accordingly, microarray analysis of Erg-restored and Ergkd/+ HSPCs from the same animal revealed enrichment of stem cell-related pathways in Ergkd/+ HSPCs. Overall, reduced Erg dosage perturbs hematopoiesis by reducing HSC numbers and impairing HSC differentiation, possibly via two Erg targets, Jun and Myc.
2017-06-20 | GSE48600 | GEO
Project description:Hematopoietic stem cells give rise to all blood lineages, can fully re-populate the bone marrow, and easily outlive the host organism. To better understand how stem cells remain fit during aging, we analyzed the proteome of hematopoietic stem and progenitor cells.
2019-05-23 | MSV000083845 | MassIVE
Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from Ahr-knockout and wild-type mice. HSC from young-adult (8 wk old) AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC. 7 samples: 3 Ahr knockout, 4 wild-type
2013-11-08 | E-GEOD-46976 | biostudies-arrayexpress
Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from 18-month-old Ahr-knockout and wild-type mice. HSC from aged AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC. 10 samples: 5 Ahr knockout, 5 wild-type
2015-03-28 | E-GEOD-67378 | biostudies-arrayexpress
Project description:Mass spectrometry results from TurboID experiments using constructs expressing TurboID only, NPM1wt-Turbo ID (N- and C-terminal fusions) and NPMc-Turbo ID fusions (N- and C-terminal fusions) transduced in primary mouse hematopoietic stem/progenitor cells from lineage-depleted mouse bone marrow.
2022-03-09 | MSV000089028 | MassIVE
Project description:The Ets transcription factor, ERG, plays a central role in definitive hematopoiesis and its overexpression in acute myeloid leukemia is associated with a stem cell signature and bad prognosis. However, little is known about the underlying mechanism by which ERG causes leukemia. Therefore we sought to identify ERG targets that participate in development of leukemia by integration of expression arrays and Chromatin immunoprecipitation. Bone marrow was collected from three transgenic ERG mice harboring a myeloid leukemia and twelve wild type mice. Nine wild type bone marrow samples were lineage depleted and pooled into 3 samples (each one consisting of three lineage negative wild type bone marrows). The resulting 9 samples were used for RNA extraction and hybridization on affymetrix microarrays.
2013-08-13 | E-GEOD-49787 | biostudies-arrayexpress
Project description:To explore the mechanisms by which DCAF8 deficiency induces functional defects in hematopoietic stem cells with an aging-like phenotype, and given DCAF8’s role as a substrate receptor in the E3 ubiquitin ligase complex, we conducted proteomic analysis on Lineage negative bone marrow cells from wild-type and Dcaf8 knockout mice. This analysis aimed to identify protein alterations, providing insights into potential substrates of DCAF8 in murine hematopoietic cells.
2025-10-04 | PXD056107 | Pride
Project description:To explore the mechanisms by which DCAF8 deficiency induces functional defects in hematopoietic stem cells with an aging-like phenotype, and given DCAF8’s role as a substrate receptor in the E3 ubiquitin ligase complex, we conducted ubiquitin proteomic analysis on bone marrow cells from wild-type and Dcaf8 knockout mice. This analysis aimed to identify ubiquitinated proteins and assess changes in ubiquitination, providing insights into potential substrates of DCAF8 in murine hematopoietic cells.
2025-10-04 | PXD056221 | Pride
Project description:To explore the mechanisms by which DCAF8 deficiency induces functional defects in hematopoietic stem cells with an aging-like phenotype, and given DCAF8’s role as a substrate receptor in the E3 ubiquitin ligase complex, we conducted ubiquitin proteomic analysis on bone marrow cells from wild-type and Dcaf8 knockout mice. This analysis aimed to identify ubiquitinated proteins and assess changes in ubiquitination, providing insights into potential substrates of DCAF8 in murine hematopoietic cells.
2025-10-04 | PXD056263 | Pride